The preparation of compounds having a 1,2-dihydroquinoline structure has been described in Patent Specifications DD 227 434 and DE 4 115 535. Other compounds having the same nucleus, variously substituted, have been used in the preparation of smoked meats (GB 1537334) or as photochemical indicators (WO 89 05994). The anti-oxidant properties of tetrahydroquinoline compounds have been used in the field of lubricants (EP 072 349). Compounds of this type have also been described as inhibitors of lipid absorption (EP 028 765).
According to Hartman""s free-radical theory of ageing (J. Gerontol., 1956, 11, 298), successive oxidation attacks create xe2x80x9coxidation stressxe2x80x9d conditions, which reflect an imbalance in the organism between the systems that produce free-radical species and the systems that are protective against those species (R. E. PACIFICI, K. J. A. DAVIES, Gerontology, 1991, 37, 166). Various defence mechanisms may act in synergy, allowing the action of the free radicals to be controlled. Those mechanisms may be enzymatic, as is the case for systems involving superoxide dismutase, catalase and glutathione peroxidase, or non-enzymatic in the case of vitamin E and vitamin C involvement. With age, however, those natural defences become less and less efficient, especially as a result of the oxidative inactivation of a large number of enzymes (A. CASTRES de PAULET, Ann. Biol. Clin., 1990, 48, 323).
It has been possible to link conditions of oxidation stress with disorders associated with ageing, namely atherosclerosis, cataract, non-insulin-dependent diabetes and cancer (M. HAYN et al., Life Science, 1996, 59, 537). The central nervous system is especially sensitive to oxidation stress because of its high oxygen consumption, the relatively low level of its anti-oxidation defences and the high iron content of some cerebral regions (S. A. BENKOVIC et al., J. Comp. Neurol. 1993, 338, 92; D. HARTMAN, Drugs Aging, 1993, 3, 60). Successive oxidation attacks therefore constitute one of the main etiological factors of cerebral ageing and associated disorders, namely Alzheimer""s disease and chronic neurodegenerative disorders, neurodegeneracies of the basal ganglia (Parkinson""s disease, Huntington""s disease,.), (B. HALLIWELL, J. Neurochem., 1992, 59, 1609).
In addition to the fact that the compounds of the present invention are new, they exhibit valuable pharmacological properties. Their anti-oxidant character, being a trap for reactive oxygenated species, especially at the level of the central nervous system, means that they can be considered for use in opposing the effects of oxidation stress, especially at the cerebral level. Most of them, moreover, have the advantage of not causing a hypothermic effect at the doses used for obtaining neuroprotective action. They will therefore be useful in the treatment of disorders associated with ageing, such as atherosclerosis and cataract, in the treatment of cancer, in the treatment of cognitive disorders, and in the treatment of acute neurodegenerative disorders, such as cerebral ischaemia and epilepsy, and in the treatment of chronic neurodegenerative disorders, such as Alzheimer""s disease, Pick""s disease and neurodegeneracies of the basal ganglia (Parkinson""s disease, Huntington""s disease).
The present invention relates especially to the compounds of the general formula (I): 
wherein:
R1 represents a hydrogen atom or a group 
xe2x80x83wherein A represents a hydrogen atom or a group xe2x80x94BNZ1Z2 in which B represents a linear or branched (C1-C6)alkylene group and Z1 and Z2 independently represent a hydrogen atom or an alkyl, (C3-C8)cycloalkyl or optionally substituted aryl group or, together with the nitrogen atom carrying them, form an optionally substituted heterocycloalkyl or heteroaryl group,
R2 and R3 each independently represents an alkyl group, a (C3-C8)cycloalkyl group, a heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a cycloalkylalkyl group, a heterocycloalkylalkyl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group or an aminoalkyl group (optionally substituted on the nitrogen atom by one or two groups selected from alkyl, cycloalkyl, aryl and arylalkyl) or
R2 and R3, together with the carbon atom carrying them, form a (C3-C8)cycloalkyl group or a monocyclic heterocycloalkyl group unsubstituted or substituted by an alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl group,
R40 represents a hydrogen atom or a group selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl or a group Q or xe2x80x94Vxe2x80x94Q wherein V represents an alkylene, alkenylene or alkynylene group and Q represents an optionally substituted (C3-C8)cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group or an optionally substituted heteroaryl group,
R41 and R5 together form a bond or each represents a hydrogen atom,
R6, R7, R8 and R9 each independently represents a hydrogen atom, a halogen atom, an alkyl group, a (C3-C8)cycloalkyl group or a group xe2x80x94OW wherein W represents a hydrogen atom or an alkyl group, an acyl group, a (C3-C8)cycloalkyl group, a heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group (provided that R6, R7, R8 and R9 cannot all simultaneously represent a hydrogen atom and that at least one of them represents a group xe2x80x94OW as defined hereinbefore),
with the proviso that:
when R2 and R3 represent an alkyl group:
if each of R6 to R9 independently represents a hydrogen atom, an alkyl group or a group xe2x80x94OW wherein W represents an alkyl group, and R41 and R5 together form a bond, then R40 is other than a hydrogen atom or an alkyl group,
if a single group xe2x80x94OW is present in the molecule and represents a hydroxy group, then R40 is other than a hydrogen atom,
if a single group xe2x80x94OW is present in the molecule and represents a methoxy group, then R40 is other than a hydroxyalkyl group,
the compound of formula (I) being other than 7-methoxy-2,2-diphenyl-1,2-dihydroquinoline,
it being understood that:
the term alkyl denotes a linear or branched chain of from 1 to 6 carbon atoms,
the term acyl denotes an alkyl-carbonyl group, alkyl being as defined hereinbefore,
the term alkenyl denotes a linear or branched chain of from 2 to 6 carbon atoms containing from 1 to 3 double bond(s),
the term alkynyl denotes a linear or branched chain of from 2 to 6 carbon atoms containing from 1 to 3 triple bond(s),
the term alkylene denotes a linear or branched bivalent group containing from 1 to 6 carbon atoms,
the term alkenylene denotes a linear or branched bivalent group containing from 2 to 6 carbon atoms and from 1 to 3 double bonds,
the term alkynylene denotes a linear or branched bivalent group containing from 2 to 6 carbon atoms and from 1 to 3 triple bonds,
the term aryl denotes a phenyl, naphthyl or biphenyl group,
the term heterocycloalkyl denotes a mono- or bi-cyclic, 4- to 11-membered group containing from 1 to 6 hetero atoms selected from nitrogen, oxygen and sulphur, it being possible for the group to contain one or more unsaturations without thereby having an aromatic character,
the term heteroaryl denotes an aromatic or partially aromatic, mono- or bi-cyclic, 4- to 11-membered group containing from 1 to 6 hetero atoms selected from nitrogen, oxygen and sulphur,
the term substituted used in respect of the expressions aryl and arylalkyl indicates that the groups concerned are substituted by one or more halogen atoms or alkyl, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)perhaloalkyl, amino (optionally substituted by 1 or 2 alkyl groups), cyano, carboxy, linear or branched (C1-C6)alkoxycarbonyl, aminocarbonyl (optionally substituted on the nitrogen atom by 1 or 2 alkyl groups), nitro or hydroxy groups,
the term substituted used in respect of the expressions alkyl, alkenyl, alkynyl and cycloalkyl indicates that such groups are substituted by one or more groups selected from hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkylthio, amino (optionally substituted by one or two alkyl groups), carboxy, nitro, cyano, linear or branched (C1-C6)alkoxycarbonyl and aminocarbonyl (optionally substituted on the nitrogen atom by one or two alkyl groups),
the term substituted used in respect of the expressions heterocycloalkyl, heteroaryl and heteroarylalkyl indicates that the groups concerned are substituted by one or more halogen atoms or alkyl, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)perhaloalkyl, amino (optionally substituted by 1 or 2 alkyl groups), cyano, carboxy, linear or branched (C1-C6)alkoxycarbonyl, aminocarbonyl (optionally substituted on the nitrogen atom by 1 or 2 alkyl groups), nitro, hydroxy or oxo groups,
enantiomers and diastereoisomers thereof, and addition salts thereof with a pharmaceutically acceptable acid or base.
Amongst the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic, camphoric and oxalic acid etc.
Amongst the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
The present invention advantageously relates to compounds of formula (I) wherein R1 represents a hydrogen atom.
Preferably, in the compounds of formula (I), R6, R7, R8 and R9 each independently represents a hydrogen atom, an alkyl group or a group xe2x80x94OW wherein W represents an alkyl, acyl or phenyl group. More especially, W represents an alkyl group.
Preferred compounds of the invention are those wherein R2 and R3 each represents an alkyl group, for example methyl.
Other preferred compounds of the invention are those wherein R2 and R3 together form an optionally substituted cycloalkyl or heterocycloalkyl group, and more especially, a cycloalkyl group, for example cyclohexyl.
In the compounds of formula (I), R40 preferably represents a hydrogen atom or a group Vxe2x80x94Q, V being more especially an alkylene group and Q being more especially a heterocycloalkyl group.
The preferred aryl group of the invention is the phenyl group.
An advantageous aspect of the invention relates to compounds of formula (I) wherein R1 represents a hydrogen atom, R2 and R3 represent an alkyl group or together form a cycloalkyl group, R40 represents a hydrogen atom or a group xe2x80x94Vxe2x80x94Q wherein V represents an alkylene group and Q represents a heterocycloalkyl group, and R6, R7, R8 and R9 each independently represents a hydrogen atom, an alkyl group or a group xe2x80x94OW wherein W represents an alkyl, acyl or phenyl group, it being understood that R6, R7, R8 and R9 cannot all represent a hydrogen atom and that at least one of them represents a group xe2x80x94OW as defined hereinbefore.
Amongst the preferred compounds of the invention there may be mentioned:
6-ethoxy-1,2-dihydroquinoline-2-spirocyclohexane,
6-ethoxy-5,7,8-trimethyl-1,2-dihydroquinoline-2-spirocyclohexane,
8-ethoxy-1,2-dihydroquinoline-2-spirocyclohexane,
5,7-diisopropyl-6-ethoxy-1,2-dihydroquinoline-2-spirocyclohexane,
5,7-dimethyl-6-ethoxy-1,2-dihydroquinoline-2-spirocyclohexane,
6-ethoxy-2,2,5,7,8-pentamethyl-1,2,3,4-tetrahydroquinoline,
5,7-diisopropyl-2,2-dimethyl-6-ethoxy-1,2,3,4-tetrahydroquinoline,
6-ethoxy-2,2,5,7-tetramethyl-1,2,3,4-tetrahydroquinoline,
6-ethoxy-5,7,8-trimethyl-1,2,3,4-tetrahydroquinoline-2-spirocyclohexane,
6-ethoxy-1,2-dihydroquinoline-2-spiro-4xe2x80x2-piperidine,
6-ethoxy-1,2-dihydroquinoline-2-spiro-4xe2x80x2-(1xe2x80x2-cyclopropylmethyl-piperidine),
2,2-dimethyl-6-ethoxy-3-(2-morpholinoethyl)-1,2-dihydroquinoline dihydrochloride,
6-tert-butoxy-1,2-dihydroquinoline-2-spirocyclohexane,
6-methoxy-1,2-dihydroquinoline-2-spirocyclohexane,
6-phenoxy-1,2-dihydroquinoline-2-spirocyclohexane,
6-ethoxy-5,7-dimethyl-1,2,3,4-tetrahydroquinoline-2-spirocyclohexane,
6-ethoxy-2,2-dimethyl-3-[2-(2,6-dioxopiperazin-4-yl)ethyl]-1,2-dihydroquinoline,
6-ethoxy-2,2-dimethyl-3-[2-(1-piperidinyl)ethyl]-1,2-dihydroquinoline.
2-[2-(6-ethoxy-2,2-dimethyl-1 2-dihydro-3-yl)ethyl]-1H-isoindole-1,3(2H)-dione,
3-[2-(6-ethoxy-2,2-dimethyl-1,2-dihydro-3-quinolenyl)ethyl]-4(3H)-quinazolinone,
6-tert-butylcarbonyloxy-1,2-dihydroquinoline-2-spirocyclohexane,
and very especially:
6-ethoxy-2,2,5,7,8-pentamethyl-1,2,3,4-tetrahydroquinoline,
6-ethoxy-1,2-dihydroquinoline-2-spirocyclohexane.
The present invention relates also to a process for the preparation of the compounds of formula (I), which is characterised in that there is used as starting material a variously substituted aniline of formula (II): 
wherein R6, R7, R8 and R9 are as defined for formula (I),
which is subjected:
either to the action, in a basic medium and optionally in the presence of a catalyst, of a halogenated acetylide of formula (III): 
xe2x80x83wherein R2 and R3 are as defined for formula (I), G represents a hydrogen atom or a trialkylsilyl group and Hal represents a halogen atom,
to yield a compound of formula (IV): 
wherein R2, R3, R6, R7, R8, R9 and G are as defined hereinbefore,
or to the action of a carbonyl compound of formula (V): 
wherein R2 and R3 are as defined for formula (I),
to yield a compound of formula (VI): 
wherein R2, R3, R6, R7, R8 and R9 are as defined hereinbefore,
which compound (VI) is subjected, in a basic medium, to the action of an acetylide of formula (III) as defined hereinbefore,
to yield a compound of formula (IV) as defined hereinbefore,
which compound of formula (IV), where applicable after cleavage of the trialkylsilyl group, is cyclised by heating in the presence of an appropriate catalyst to yield a compound of formula (I/a): 
a particular case of the compounds of formula (I) wherein R2, R3, R6, R7, R8 and R9 are as defined hereinbefore,
which:
 either may be subjected to a reduction reaction to yield a compound of formula (I/b): 
xe2x80x83a particular case of the compounds of formula (I) wherein R2, R3, R6, R7, R8 and R9 are as defined hereinbefore,
which compounds of formula (I/a) and (I/b), after chloroformylation of the ring nitrogen, are subjected to the action of an amine of formula (VII):
H2Nxe2x80x94Axe2x80x83xe2x80x83(VII),
wherein A is as defined for formula (I),
to yield a compound of formula (I/c): 
wherein R2, R3, R6, R7, R8, R9 and A are as defined hereinbefore, and R41 and R5 are as defined for formula (I),
 or, after protection of the ring nitrogen atom, may be subjected successively to a hydroxyhalogenation reaction and to an oxidation reaction in the benzyl position to yield a compound of formula (VIII): 
wherein R2, R3, R6, R7, R8 and R9 are as defined hereinbefore, Hal represents a halogen atom and P is a protecting group for the ring nitrogen (for example an acetyl, trifluoroacetyl, tert-butoxycarbonyl or benzyloxycarbonyl group),
which is subjected to a nucleophilic substitution reaction to yield a compound of formula (IX): 
wherein R2, R3, R6, R7, R8, R9 and P are as defined hereinbefore and Y represents either a group R40, which is as defined for formula (I) but is other than a hydrogen atom, or a precursor of such a group,
which, after deprotection of the ring nitrogen, is subjected to a reduction reaction of the carbonyl function, followed by an elimination reaction to yield a compound of formula (X): 
wherein R2, R3, R6, R7, R8, R9 and Y are as defined hereinbefore,
which compound of formula (X) may, when Y is a precursor of a group R40 as defined hereinbefore, be subjected to a succession of conventional reactions directed at yielding a compound of formula (I/d): 
a particular case of the compounds of formula (I) wherein R2, R3, R6, R7, R8, R9 and R40 are as defined hereinbefore,
which may be reduced to yield a compound of formula (I/e): 
a particular case of the compounds of formula (I) wherein R2, R3, R40, R6, R7, R8 and R9 are as defined hereinbefore,
which compounds (I/d) and (I/e), after chloroformylation of the ring nitrogen, are subjected to the action of an amine of formula (VII) as defined hereinbefore to yield a compound of formula (I/f): 
wherein R2, R3, R6, R7, R8, R9 and A are as defined hereinbefore, R40 has the same meanings as in formula (I) other than a hydrogen atom, and R4 and R5 are as defined for formula (I),
the compounds (I/a) to (I/f) constituting the totality of the compounds of formula (I):
which may be, if necessary, purified according to a conventional purification technique,
the stereoisomers of which are, where appropriate, separated according to a conventional separation technique,
which are, if desired, converted into their addition salts with a pharmaceutically acceptable acid or base.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) alone or in combination with one or more inert, non-toxic excipients or carriers.
Amongst the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral and nasal administration, tablets or dragxc3xa9es, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels etc.
The dosage used varies according to the sex, age and weight of the patient, the nature and the severity of the disorder and the administration route, which may be oral, nasal or parenteral. Generally, the unit dose ranges from 0.1 to 500 mg for a treatment in from 1 to 3 administrations per 24 hours.
The following Examples illustrate the invention but do not limit it in any way.
The starting materials used are known products or are prepared according to known procedures.
Step 1:
2-Ethoxy-1,3,4-trimethylbenzene
734 mmol (101.5 g) of potassium carbonate and 917 mmol (143.1 g) of ethyl iodide are added in succession to a solution of 367 mmol (50 g) of 2,3,6-trimethylphenol in 1500 ml of acetonitrile. The whole is heated at reflux for 48 hours. The reaction mixture is subsequently cooled and then filtered and the filtrate is concentrated. The residue obtained is dissolved in ethyl acetate and washed with water and then with 10% aqueous sodium chloride solution. After drying the organic phase and then concentrating, an oily residue is obtained which is purified by chromatography on silica gel, using a petroleum ether: ethyl acetate mixture 95:5 as eluant, to yield the expected product.
Step 2:
4-Ethoxy-3,5,6-trimethyl-iodobenzene
222 mmol (50 g) of N-iodosuccinimide are added to a solution of 171 mmol (28.03 g) of the compound described in the above Step in 650 ml of acetonitrile and the whole is heated at reflux for 24 hours. The solvent is then evaporated off in vacuo and the residue is taken up in ether. The solution is washed with saturated NaHCO3 solution and then with 10% aqueous sodium chloride solution. The organic phase is dried and concentrated. The oily residue obtained is purified by chromatography on silica gel, using a petroleum ether ethyl acetate mixture 95:5 as eluant, to yield the expected product.
Step 3:
4-Ethoxy-3,5,6-trimethylaniline
0.46 mmol (0.426 g) of Pd2(dba)3 and 1.39 mmol (0.947 g) of BINAP are introduced into a 1-litre round-bottomed flask under an inert atmosphere. In a second round-bottomed flask. 46.5 mmol (13.5 g) of the compound described in the above Step, 65.1 mmol (6.26 g) of sodium tert-butanolate, 65.1 mmol (17.21 g) of 18 crown 6 and 65.8 mmol (10.12 g) of benzophenone imine are dissolved in 250 ml of anhydrous THF. The solution in the second round-bottomed flask is introduced into the round-bottomed flask containing the catalytic system with the aid of a cannula. The whole is heated at 60xc2x0 C. for 3 hours and then the reaction mixture is diluted with ether. The precipitate formed is filtered over fritted glass and the filtrate is then evaporated. The residue obtained is redissolved in 300 ml of THF. 30 ml of hydrochloric acid solution (2N) are added thereto and the solution is stirred at ambient temperature for 1 hour. The whole is then diluted with excess hydrochloric acid (1N) and a heptane:ethyl acetate mixture 2:1. The aqueous phase is separated and then neutralised using 1M sodium hydroxide solution. After extracting with dichloromethane, drying the organic phase and evaporating off the solvent, the expected product is obtained.
Step 1:
2,6-Diisopropyl-4-nitrophenol
78.3 mmol (4.93 g) of fuming nitric acid are added dropwise to a solution, cooled to 0xc2x0 C., of 53.9 mmol (9.62 g) of 2,6-diisopropylphenol in 350 ml of acetic acid. The reaction mixture is stirred at 0xc2x0 C. for 1 hour 30 minutes and is then poured into a mixture of ethyl acetate and ice. The organic phase is isolated and then washed with water. After drying and evaporating off the solvent, an oily residue is recovered which is purified by chromatography on silica gel using a petroleum ether: ethyl acetate mixture 9:1 as eluant.
Step 2:
2,6-Diisopropyl-1-ethoxy-4-nitrobenzene
The expected product is obtained according to the procedure described in Step 1 of Preparation A, starting from the compound described in the above Step.
Step 3:
3,5-Diisopropyl-4-ethoxyaniline
A solution of 19.9 mmol (5.0 g) of the compound described in the above Step in 135 ml of absolute ethanol in the presence of 1.5 g of palladium-on-carbon (10%) is placed under 1 atm. of hydrogen at ambient temperature for 4 hours. After that period, the reaction mixture is filtered and then the filtrate is concentrated to yield the expected compound.
Step 1:
3,5-Dimethyl-4-ethoxy-nitrobenzene
300 mmol (326 g) of caesium carbonate and 374 mmol (58.5 g) of ethyl iodide are added in succession to a solution of 149.5 mmol (25 g) of 2,6-dimethyl-4-nitrophenol in 1300 ml of acetonitrile. The whole is heated at reflux under an inert atmosphere for 15 hours. The reaction mixture is subsequently cooled and then filtered, and the filtrate is evaporated. The residue is dissolved in ethyl acetate and washed with water and then with 10% aqueous sodium chloride solution. The expected product is obtained by drying the organic phase and then concentrating.
Step 2:
3,5-Dimethyl-4-ethoxyaniline
A solution of 149.5 mmol (29.19 g) of the compound described in the above Step in 1000 ml of absolute ethanol in the presence of 9.4 g of palladium-on-carbon (10%) is placed under 1 atm. of hydrogen at ambient temperature for 4 hours. After that period, the reaction mixture is filtered and then the filtrate is concentrated to yield the expected compound.
Step 1:
1-tert-Butoxy-4-nitrobenzene
43.79 mmol of N-N-dimethylformamide di-tert-butyl acetal are added, at ambient temperature, to a solution of 10.78 mmol (1.5 g) of 4-nitrophenol in 10 ml of toluene. The reaction mixture is heated at reflux, with vigorous stirring, for 5 hours. The reaction mixture is diluted with ethyl acetate and then washed with water, with saturated aqueous sodium bicarbonate solution and then with 10% aqueous sodium chloride solution. The expected product is obtained by drying the organic phase and then concentrating.
Step 2:
4-tert-Butoxy-aniline
A solution of 4.61 mmol (0.90 g) of the compound described in the above Step in 15 ml of absolute ethanol containing 24.65 mmol (2.12 g) of cyclohexene and 0.29 g of palladium-on-carbon (10%) is heated at reflux, with vigorous stirring, for 2 hours. After that period, the reaction mixture is filtered and then the filtrate is concentrated to yield the expected compound.
Step 1:
1-tert-Butylcarbonyloxy-4-nitrobenzene
161.1 mmol (19.48 g) of pivaloyl chloride are added, at 0xc2x0 C., to a solution of 107.8 mmol (15 g) of 4-nitrophenol in 250 ml of pyridine. The reaction mixture is stirred for 72 hours at ambient temperature. The reaction mixture is evaporated in vacuo and the oily residue is diluted with ethyl acetate and then washed with aqueous hydrochloric acid solution (0.1N) and then with 10% aqueous sodium chloride solution. The expected product is obtained by drying the organic phase and then concentrating.
Step 2:
4-tert-Butylcarbonyloxy-aniline
A solution of 95.41 mmol (21.30 g) of the compound described in the above Step in 1200 ml of a 4/1 mixture of methanol and acetic acid containing 573 mmol (32.00 g) of iron is heated at 65xc2x0 C. for 20 hours. After that period, the reaction mixture is filtered and the filtrate is then concentrated to yield an oily residue which is diluted with ethyl acetate and washed with 10% aqueous sodium bicarbonate solution and then with 10% aqueous sodium chloride solution. The expected product is obtained by drying the organic phase and then concentrating.